Systems and methods for mapping binding site volumes in macromolecules

Abstract

Systems, methods, and apparatus for evaluating a binding site of a macromolecule are disclosed in which the binding site is identified and a binding site volume map of the binding site is constructed. The binding site volume map has a surface with a plurality of regions. Each respective region in the plurality of regions of the surface is classified based upon a first characteristic that is complementary to a second characteristic of a portion of the macromolecule that is nearest to the respective region, thereby creating an interaction map. Systems, methods, and apparatus for comparing macromolecules are also disclosed in which a binding site volume map is constructed for each of the macromolecules. Then, a composite binding site volume map that comprises a volumetric combination of each of the binding site volume maps is constructed. An interaction map can be constructed from the composite binding site volume map.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of Invention[0002]This invention relates to processes, apparatus, media and signals for mapping binding pocket volumes in macromolecules such as proteins and nucleic acids.[0003]2. Description of Related Art[0004]With the advent of several high-resolution macromolecular structures deposited in the Brookhaven Protein Databank1 (PDB), structure-based drug design is more feasible. An example of the application of structure-based design techniques is the development of novel human immunodeficiency virus 1 (HIV-1) protease inhibitors. See, Rutenber et al., 1993, J. Biol. Chem. 268: 15343-15346; Ghosh et al., 1994, J. Med. Chem. 37: 2506-2508; and Lam et al., 1994, Science 263: 380-384. A prerequisite for the docking of small molecule ligands is the determination of the site where the ligand interacts with the protein. Such binding sites for small molecule ligands are pockets (alternatively and interchangeably named clefts, grooves, active sites) ...

AI Technical Summary

Benefits of technology

[0008]The present invention provides processes, apparatus, media and signals that have many useful applications including, but not limited to, identifying vectors for ligand design, quick generation of ligand selectivity hypotheses, and the identification of common volumes in the binding pockets of different macromolecules for addressing multiple targets. In one embodiment, quick identification of macromolecule binding sites using alpha spheres is followed by mapping of the binding site volume graphically as well as numerically. The graphical volume map defines the volume available to a potential ligand in the macromolecule binding site. This volume map can be enhanced through, for example, color coding to form an interaction map that defines the expected interaction types (e.g. hydrophobic, electrostatic, etc.) that the ligand atoms need to adopt in order to achieve complementarity with the binding site of the macromolecule. Intersection of the volume maps of related macromolecules allows for the identification of unique regions that can be exploited to achieve selectivity.

Problems solved by technology

A manual definition of binding sites is laborious for several reasons.

In most cases it is difficult to define exactly where a binding site ends and free space begins.

Macromolecules may have surface depressions of various sizes and a manual inspection may fail to find all relevant binding sites but the largest one.

A manual definition is also impractical when large sets of macromolecular structures must be processed (e.g., for statistical studies of pocket characteristics).

However, if this ligand also specifically binds to the active site of many other types of kinases other than the target kinase (e.g., the kinase CDK2, etc.), the ligand is likely to be toxic because it would interfere with a large number of molecular pathways in the cell that are regulated by these other kinases.

A ligand that specifically binds many different macromolecules in this way does not have the desired selectively.

However, one deficiency with such known programs is that they do not provide convenient ways to analyze ligand selectivity.

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